Breast Cancer Stem Cell Potency of Nickel(II)‐Polypyridyl Complexes Containing Non‐steroidal Anti‐inflammatory Drugs

We report the breast cancer stem cell (CSC) potency of two nickel(II)‐3,4,7,8‐tetramethyl‐1,10‐phenanthroline complexes, 1 and 3, containing the non‐steroidal anti‐inflammatory drugs (NSAIDs), naproxen and indomethacin, respectively. The nickel(II) complexes, 1 and 3 kill breast CSCs and bulk breast cancer cells in the micromolar range. Notably, 1 and 3 display comparable or better potency towards breast CSCs than salinomycin, an established CSC‐active agent. The complexes, 1 and 3 also display significantly lower toxicity towards non‐cancerous epithelial breast cells than breast CSCs or bulk breast cancer cells (up to 4.6‐fold). Mechanistic studies suggest that 1 and 3 downregulate cyclooxygenase‐2 (COX‐2) in breast CSCs and kill breast CSCs in a COX‐2 dependent manner. Furthermore, the potency of 1 and 3 towards breast CSCs decreased upon co‐treatment with necroptosis inhibitors (necrostatin‐1 and dabrafenib), implying that 1 and 3 induce necroptosis, an ordered form of necrosis, in breast CSCs. As apoptosis resistance is a hallmark of CSCs, compounds like 1 and 3, which potentially provide access to alternative (non‐apoptotic) cell death pathways could hold the key to overcoming hard‐to‐kill CSCs. To the best of our knowledge, 1 and 3 are the first compounds to be associated to COX‐2 inhibition and necroptosis induction in CSCs.